Abstract. Depression is consistently one of the top causes of morbidity and mortality, and veterans are afflicted more commonly than non-veterans. In addition, veterans are more than twice likely to die from depression-related suicide than the general population. Despite current antidepressant medications, a disappointingly large number of patients are refractory to current treatments, all of which target similar mechanisms. Thus, new medications with novel mechanisms of action are urgently needed. Using animal models that can predict antidepressant and anti-anxiety effects in humans, we identified a novel molecule in depression and anxiety- related behaviors, the acid-sensing ion channel 1a (ASIC1a). Pharmacologically inhibiting and genetically disrupting ASIC1a in mice produced antidepressant-like effects in the forced swim test, tail suspension test, and following chronic unpredictable stress. Moreover, the effects were independent of and additive to several currently used antidepressant medications. Disrupting ASIC1a also reduced conditioned and unconditioned fear behaviors, which model post-traumatic stress disorder (PTSD) and other anxiety disorders. Together these findings suggest the exciting possibility that targeting ASIC1a will relieve depression and anxiety through a novel mechanism of action. To take full advantage of this possibility we need to know more about how ASIC1a is activated in the brain. The exquisite sensitivity of ASIC1a to low extracellular pH suggests that acidic pH might play an important signaling role. We hypothesize that emotionally distressing stimuli lower pH in the amygdala, which in turn activates ASIC1a to promote stress responses including depression and anxiety-related behaviors. To test this hypothesis we propose to answer the following questions: 1) Does manipulating ASIC1a pH sensitivity alter its effects on depression-related behavior? 2) Does altering the expression of ASIC1a and other ASIC subunits influence depression-related behavior? And, 3) can pH be therapeutically targeted to reduce depression? Our planned experiments take advantage of several recent advances including: our ability to measure brain pH in behaving mice with a fiber optic pH sensor, and our ability to alter the pH sensitivity of ASIC1a channels and assess the behavioral consequences. If pH dependent signaling contributes to depression and anxiety, then manipulating pH or ASICs could provide novel therapeutic opportunities that may be rapidly translated to human research and treatment. For example, a number of techniques can be used to safely alter human brain pH, and might be used to intervene in depression and in other psychiatric consequences of severe emotional stress. PUBLIC HEALTH RELEVANCE: Depression is a leading cause of disability and mortality that affects veterans even more frequently than non-veterans. Moreover, veterans are more than twice as likely to die from depression-related suicide. Unfortunately, a large number of veterans do not respond to current medications. Thus, new treatments with novel mechanisms of action are desperately needed. Using animal models that can predict antidepressant efficacy in humans, we found a novel ion channel that when disrupted or inhibited produces antidepressant and anti-anxiety-like effects in mice. This channel, called acid-sensing ion channel-1a (ASIC1a), is activated by acidic pH. The pH sensitivity of these channels, coupled with evidence that pH fluctuations occur in the brain with neural activity, suggests that pH might play an important signaling role in the brain to promote depression and anxiety. In this proposal, we will determine the contribution of brain pH to ASIC1a channel activity, and test whether ASIC1a and brain pH might be targeted to reduce depression.